Adenosine induces apoptosis through TNFR1/RIPK1/P38 axis in colon cancer cells
Shunji Yu1, Daisen Hou2, Ping Chen2
1Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China; Institutes of Biomedical Sciences and Department of Immunology of Shanghai Medical School, Fudan University, Shanghai 200032, China.
Abstract:
Adenosine, a metabolite of ATP, ubiquitously exists in a wide range of organs and tissues. We previously reported that adenosine was implicated in apoptosis in many cancer cells by extrinsic and/or intrinsic pathways. Here, we found that adenosine suppresses the cell growth by induction of apoptosis of human colonic cancer cells through a novel mechanism. Adenosine suppresses the cell growth of human SW620 and SW480 colon cells in an adenosine transporter and adenosine kinase dependent manner. Moreover, the cell growth suppression is induced by apoptosis through activation of caspase-3 and PARP, and accumulation of ROS in cells. Importantly, we found that adenosine increases the expression of TNFR1 and RIPK1 and the phosphorylation of p38. Knockdown of TNFR1 or RIPK1 impairs the activation of p38, blocks the cleavage of PARP, and provides partially, yet significantly protection from cell death, including reducing the ROS generation in the colon cancer cells. These results indicate that a TNFR1/RIPK1/P38 axis is present in adenosine-induced apoptosis of colonic cancer cells. This axis triggers apoptosis and plays crucial roles in relay of the death signaling. Our study also provides additional experimental evidence for adenosine as a potent therapeutic drug in cancer therapy.
Insights
Adenosine induces apoptosis and suppresses colon cancer cell growth via a novel TNFR1/RIPK1/p38 pathway. This mechanism, dependent on adenosine transporters and kinase, offers potential for new cancer therapies.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Adenosine, an ATP metabolite, is involved in apoptosis in various cancer cells.
- Previous research indicated adenosine's role in cancer cell apoptosis through extrinsic and intrinsic pathways.
Purpose of the Study:
- To elucidate the novel mechanism by which adenosine suppresses human colonic cancer cell growth.
- To investigate the role of the TNFR1/RIPK1/p38 axis in adenosine-induced apoptosis.
Main Methods:
- Utilized human colon cancer cell lines (SW620 and SW480).
- Investigated adenosine transporter and kinase dependency.
- Assessed apoptosis markers (caspase-3, PARP cleavage), reactive oxygen species (ROS) accumulation.
- Examined the expression of TNFR1, RIPK1, and p38 phosphorylation.
- Performed knockdown experiments for TNFR1 and RIPK1.
Main Results:
- Adenosine suppressed colon cancer cell growth via apoptosis, dependent on adenosine transporter and kinase.
- Apoptosis was mediated by caspase-3 and PARP activation and ROS accumulation.
- Adenosine increased TNFR1 and RIPK1 expression and p38 phosphorylation.
- TNFR1/RIPK1 knockdown partially protected cells from death, reduced ROS, and impaired p38 activation.
Conclusions:
- A novel TNFR1/RIPK1/p38 signaling axis mediates adenosine-induced apoptosis in colon cancer cells.
- This axis is crucial for relaying death signals and plays a significant role in adenosine's anti-cancer effects.
- Adenosine shows promise as a therapeutic agent for colon cancer treatment.
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